# Investigating the role of dysfunctional histone H3.3 in driving early neuronal development and pediatric high-grade gliomas

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $426,431

## Abstract

Summary Statement/Abstract
 Pediatric brain tumors are the most common solid tumors in children, with approximately 5000 new cases
diagnosed per year in the United States. Around 17% of brain tumors in children age 0–14 years are high-grade
gliomas (HGGs), which are currently incurable. The lack of effective treatments highlights the urgent need to
identify mechanism-based therapeutic approaches. Substantial experimental evidence has recently revealed
that H3.3-G34R–harboring pediatric HGGs (pHGGs) exhibit high genomic instability and high-level expression
of neuronal markers, indicating that these tumors represent a distinct subtype of pHGG compared with other
types, including the one with an H3.3-K27M mutation. More than 90% of H3.3-G34R gliomas also harbor ATRX
loss-of-function mutations. Using a newly established genetically engineered murine model (GEMM), we
demonstrated that H3.3-G34R mutation and ATRX deletion in premalignant neural stem cells (PM-NSCs) with
the Trp53-/- background could strongly promote gliomagenesis. These tumors exhibit typical features of human
H3.3-G34R–harboring pHGGs, so this GEMM provides us with a faithful tool for studying the molecular
mechanisms underlying the synergistic effects of H3.3-G34R mutation and ATRX deletion and for identifying
novel therapeutic targets. We have found that H3.3-G34R mutation changes histone modifications both locally
and globally and leads to high expression of FoxD1 and HoxA1, transcription factors essential for early neuronal
development. Given that enrichments of FoxD1 and HoxA1 are associated with worse prognosis in glioma
patients, they provide 2 novel therapeutic targets for pHGGs. In addition, we found that ATRX loss leads to ALT
activation, which makes tumor cells sensitive to perturbation of their mitochondrial function. On the basis of these
observations, we hypothesize that distinctive epigenetic profiles induced by H3.3-G34R mutation and ATRX loss
drive gliomagenesis and lead to targetable vulnerabilities involving dysfunctional telomeres and impaired
mitochondrial activity. To test this hypothesis, we plan to 1) determine the roles of FoxD1 and HoxA1 in H3.3-
G34R–driven gliomagenesis, 2) define the therapeutic vulnerability induced by ATRX deficiency in pHGGs, and
3) elucidate the synergistic effect of H3.3-G34R mutation and ATRX loss on epigenetic reprogramming in
gliomas. The completion of the proposed studies will not only fill the gaps in our knowledge of how H3.3-G34R
and ATRX loss change the epigenome to lead to normal neuronal development and gliomagenesis, but also—
and more importantly—contribute to the development of therapeutic strategies that target pHGGs and provide
insights into the role of epigenetic regulation in brain development and gliomagenesis.

## Key facts

- **NIH application ID:** 10296014
- **Project number:** 1R01NS119493-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jian Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,431
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296014

## Citation

> US National Institutes of Health, RePORTER application 10296014, Investigating the role of dysfunctional histone H3.3 in driving early neuronal development and pediatric high-grade gliomas (1R01NS119493-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10296014. Licensed CC0.

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